EP0404039A1 - Pharmaceuticals containing di-tert.butylhydroxyphenyl-derivatives and new derivatives - Google Patents

Pharmaceuticals containing di-tert.butylhydroxyphenyl-derivatives and new derivatives Download PDF

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EP0404039A1
EP0404039A1 EP90111501A EP90111501A EP0404039A1 EP 0404039 A1 EP0404039 A1 EP 0404039A1 EP 90111501 A EP90111501 A EP 90111501A EP 90111501 A EP90111501 A EP 90111501A EP 0404039 A1 EP0404039 A1 EP 0404039A1
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Prior art keywords
tert
butyl
hydroxyphenyl
ethyl
amide
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German (de)
French (fr)
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EP0404039B1 (en
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Bruno Dr. Dreckmann-Behrendt
Ernst-Christian Dr. Witte
Hans Peter Dr. Wolff
Hans Alois Dr. Dresel
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Roche Diagnostics GmbH
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Roche Diagnostics GmbH
Boehringer Mannheim GmbH
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
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    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/48—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
    • C07C275/20—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C275/24—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing six-membered aromatic rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/43—Y being a hetero atom
    • C07C323/44—X or Y being nitrogen atoms
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    • C07C323/46—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms
    • C07C323/48—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having at least one of the nitrogen atoms, not being part of nitro or nitroso groups, further bound to other hetero atoms to nitrogen atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07C335/00—Thioureas, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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Definitions

  • the present invention relates to di-tert-butylhydroxyphenyl derivatives (BHT derivatives) of the general formula I.
  • BHT derivatives di-tert-butylhydroxyphenyl derivatives of the general formula I.
  • a and C which can be the same or different, a bond or a saturated or unsaturated hydrocarbon chain with 1-8 C atoms, which can be branched or unbranched and interrupted by heteroatoms such as oxygen or sulfur
  • B represents one of the following groups: in which X oxygen or sulfur, R, R ′, which can be the same or different, Is hydrogen or C1-C4 alkyl, preferably methyl or ethyl, and D stands for an unsaturated or saturated, branched or unbranched chain with one to 10 carbon atoms, which can be interrupted by one or more heteroatoms - preferably by sulfur.
  • D preferably represents a -CH2-, -CH2-CH2-, (CH2) 4-, (CH2) 6-, -CH2-CH2-O-CH2-CH2- or -CH2-CH2-S-CH2-CH2- group represents.
  • the compounds of general formula I are used as medicaments, in particular as antiarteriosclerotics.
  • Di-butylated hydroxyphenyl derivatives which have amide, ester, amine and urea structures between two phenyl nuclei in the spacer, have been known for a long time for stabilizing organic material.
  • Antioxidants are substances that - added in small amounts - cause a temporary standstill or at least a considerable delay in the oxidative processes in the product to be protected.
  • the 2,6-di-tert-butylphenyl derivatives known to date from the literature are suitable as stabilizers against thermooxidative or light-induced degradation for polyolefin copolymers, polystyrene, acrylic butadiene styrene, polyvinyl chloride, polyester, cellulose derivatives, elastomers, Adhesives, technical Greases, mineral oils, paints and paints.
  • Some connections such as Irganox 1076 [octadecyl 3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionate] received FDA approval for food packaging.
  • a substance with a sterically hindered alkylphenol is already used as a pharmaceutical.
  • Probucol originally used in the plastics and rubber industry as a plasticizer or antioxidant, shows a hypocholesterolemic effect in mice, rats, dogs, monkeys and in humans.
  • the reduction in serum cholesterol is associated with a reduced excretion of neutral sterols, total sterols and bile acids in the faeces, while cholesterol-7-alpha-hydroxylase activity is reduced at the same time.
  • the antiatherosclerotic effect of Probucol which can be demonstrated in animal experiments, is based on its property as an antioxidant: D. Steinberg et al. were able to show in in vivo experiments on WHHL rabbits that probucol prevents the oxidative modification of the LDL particles and the formation of macrophagocytic foam cells rich in cholesterol esters in early lesions of the artery wall. (D. Steinberg et al., N Engl J Med 320, 915-924 (1989))
  • the compounds according to the invention are stabilizers of lipoprotein particles and block the reacylation of LDL cholesterol in macrophages. They are therefore suitable on their own or in combination with antihyperlipidemics for the prophylaxis and therapy of diseases which are caused by increased or changed serum cholesterol, such as coronary heart diseases, atherosclerosis, hyperlipoproteinemia and similar diseases.
  • the compounds of the general formula I are mixed in a manner known per se with suitable pharmaceutical carriers, flavorings, flavors and colors and shaped, for example, as tablets or dragées or with the addition of appropriate auxiliaries in water or oil, such as olive oil, for example. suspended or dissolved.
  • the substances of the general formula I can be administered orally and parenterally in liquid or solid form.
  • Water is preferably used as the injection medium, which contains the stabilizers, solubilizers and / or buffers customary for injection solutions.
  • Such additives are e.g. Tartrate or borate buffers, ethanol, dimethyl sulfoxide, complexing agents (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation or polyethylene derivatives of sorbitan hydrides.
  • Solid carriers are e.g. Starch, lactose, mannitol, methyl cellulose, talc, highly disperse silica, higher molecular fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats or solid high molecular weight polymers (such as polyethylene glycols).
  • Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.
  • the dosage administered depends on the age, health and weight of the recipient, the extent of the disease, the type of further treatments which may be carried out at the same time, the frequency of the treatments and the type of effect desired.
  • the daily dose of the active compound is usually 0.1 to 10 mg / kg body weight.
  • Di-butylated hydroxyphenyl derivatives of the formula I with at least one carbonyl group as amide or urea and their derivatives can be obtained by known synthetic processes, for example by reacting a carboxylic acid or a derivative (formula II) with an amine of the general formula III in which A and C and the substituent R have the meaning given in formula I.
  • the reaction is usually carried out in an inert solvent such as a hydrocarbon, dimethylformamide or in ether.
  • an inert solvent such as a hydrocarbon, dimethylformamide or in ether.
  • Equimolar amounts of amine and carboxylic acid are preferably used in the presence of equimolar amounts of a base such as a tert. organ.
  • Amine prefers triethylamine, alkali bicarbonate, hydroxide or carbonate.
  • the acid chloride or an ester can serve as derivatives of the carboxylic acid (formula II).
  • the presence of POCl3, SOCl2 or PCl3 is usually necessary for the reaction of a carboxylic acid ester with the amine, a basic catalyst, preferably an alkali alcoholate.
  • a basic catalyst preferably an alkali alcoholate.
  • the reaction of the carboxylic acid with an amine in a solvent such as xylene is also possible by heating under reflux on a water separator.
  • the urea derivatives can by reacting the amine of the general formula III can be represented with phosgene. An excess of amine is used.
  • Symmetrical urea derivatives can also be prepared by carbonylation of primary amines (arylamines and alkylamines) with carbon monoxide in the presence of a catalyst such as selenium or sulfur (cf. Sonoda et al., J.Am. Chem. Soc., 93 , 6344 (1971) and Franz et al. J. Org. Chem. 26 , 3309 (1961).
  • a catalyst such as selenium or sulfur
  • Symmetrical thioureas are also formed by the action of carbon disulphide on amines, preferably aromatic amines, with elimination of hydrogen sulfide. Alcohol and acetone have proven to be suitable solvents (cf. Houben-Weyl IX, 885 and Deposited. Doc., Viniti 6343-82, 93-8, CA 100 (19): 156 325 d).
  • the thioamide and thiourea derivatives described in the present invention can also be prepared from the carbonyl compounds with phosphorus pentasulfide.
  • the invention also relates to new compounds of the formula I, in particular the following compounds: Preferred compounds of the general formula I: N- [2- [3,5-di-tert-butyl-4-hydroxyphenyl] ethyl] -3,5-di-tert-butyl-4-hydroxybenzamide 3,5-di-tert-butyl-4-hydroxyphenylacetic acid- (3,5-di-tert-butyl-4-hydroxyphenyl) methyl amide 3,3'-Thiobis [N - [[3,5-di-tert-butyl-4-hydroxyphenyl] ethyl] propionic acid amide 3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionic acid- [2- (3,5-di-tert-butyl-4-hydroxyphenyl) ethyl amide 3- (3,5-di-tert-butyl-4-hydroxyphenyl) cinnamic acid- [2- (3,
  • the starting materials are known or, if they are new, can be prepared in a manner known per se in analogy to the known compounds.

Abstract

Pharmaceuticals containing a compound of the formula I <IMAGE> in which A, B, C have the meaning stated in the claims, as antiarteriosclerotics, and compounds of the formula I, are described.

Description

Die vorliegende Erfindung betrifft Di-tert.-Butylhydroxy­phenyl-Derivate (BHT-Derivate) der allgemeinen Formel I

Figure imgb0001
in der
A und C, die gleich oder verschieden sein können,
eine Bindung oder eine gesättigte oder ungesättigte Kohlenwasser­stoffkette mit 1-8 C-Atomen, die verzweigt oder unverzweigt sowie durch Heteroatome wie z.B. Sauerstoff oder Schwefel unterbrochen sein kann
und B eine der folgenden Gruppen darstellt:
Figure imgb0002
Figure imgb0003
 in denen
X Sauerstoff oder Schwefel,
R,R′, welche gleich oder verschieden sein können,
Wasserstoff oder C₁-C₄ Alkyl, bevorzugt Methyl oder Ethyl, bedeuten,
und
D für eine ungesättigte oder gesättigte, verzweigte oder unverzweigte Kette mit ein bis 10 C-Atomen, welche durch ein oder mehrere Heteroatome - bevorzugt durch Schwefel - unterbrochen sein kann, steht.The present invention relates to di-tert-butylhydroxyphenyl derivatives (BHT derivatives) of the general formula I.
Figure imgb0001
 in the
A and C, which can be the same or different,
a bond or a saturated or unsaturated hydrocarbon chain with 1-8 C atoms, which can be branched or unbranched and interrupted by heteroatoms such as oxygen or sulfur
and B represents one of the following groups:
Figure imgb0002
Figure imgb0003
 in which
X oxygen or sulfur,
R, R ′, which can be the same or different,
Is hydrogen or C₁-C₄ alkyl, preferably methyl or ethyl,
and
D stands for an unsaturated or saturated, branched or unbranched chain with one to 10 carbon atoms, which can be interrupted by one or more heteroatoms - preferably by sulfur.

Bevorzugte Bedeutungen von A bzw. C sind Valenz, -CH₂-CH₂-,

Figure imgb0004
oder -CH=CH-.Preferred meanings of A and C are valence, -CH₂-CH₂-,
Figure imgb0004
 or -CH = CH-.

D stellt bevorzugt eine -CH₂-, -CH₂-CH₂-, (CH₂)₄-, (CH₂)₆-, -CH₂-CH₂-O-CH₂-CH₂- oder -CH₂-CH₂-S-CH₂-CH₂- Gruppe dar.D preferably represents a -CH₂-, -CH₂-CH₂-, (CH₂) ₄-, (CH₂) ₆-, -CH₂-CH₂-O-CH₂-CH₂- or -CH₂-CH₂-S-CH₂-CH₂- group represents.

Die Verbindungen der allgemeinen Formel I finden aufgrund ihrer antioxidierenden Eigenschaften, stabilisierenden Wirkung auf Lipoproteine und Hemmwirkung auf die Reacy­lierung des LDL-Cholesterins in Makrophagen Verwendung als Arzneimittel, insbesondere als Antiarteriosklerotica.Because of their antioxidant properties, stabilizing effect on lipoproteins and inhibitory effect on the reacylation of LDL cholesterol in macrophages, the compounds of general formula I are used as medicaments, in particular as antiarteriosclerotics.

Desweiteren wirken sie antiinflammatorisch, cytoprotektiv sowie antiasthmatisch. Sie können auch als Inhibitoren der Reperfusionsabhängigen Lipidperoxidation und als Stabili­satoren des "lung surfactant factor" eingesetzt werden.Furthermore, they have an anti-inflammatory, cytoprotective and anti-asthmatic effect. They can also be used as inhibitors of reperfusion-dependent lipid peroxidation and as stabilizers of the "lung surfactant factor".

Di-butylierte Hydroxyphenyl-Derivate, welche zwischen zwei Phenylkernen im Spacer Amid-, Ester-, Amin- und Harn­stoffstrukturen haben, sind seit längerer Zeit bereits zum Stabilisieren von organischem Material bekannt.Di-butylated hydroxyphenyl derivatives, which have amide, ester, amine and urea structures between two phenyl nuclei in the spacer, have been known for a long time for stabilizing organic material.

So beschreibt beispielsweise das US-Patent US-PS 3.584.047 Benzamide und Phenylalkancarbonsäureamide sowie die DE-A-­27 21 398 (Ciba-Geigy) Phenol-Derivate mit Amidstrukturen in der Seitenkette.For example, US Pat. No. 3,584,047 describes benzamides and phenylalkanecarboxamides and DE-A-27 21 398 (Ciba-Geigy) phenol derivatives with amide structures in the side chain.

Auch Harnstoffe sowie Thioharnstoffe wurden bereits in der Literatur z.B. als Antioxidantien von T-6 Ölen beschrieben (Oxid. Commun. 5 (1-2), 115 - 28 [CA 102: 9267z] und Neftekhimiya 24 (2), 246 [CA 101: 40727c] sowie Neftekhimiya 27 (5), 703-9) [CA 108: 97496a].Urea and thioureas have also been described in the literature, for example as antioxidants of T-6 oils (Oxid. Commun. 5 (1-2), 115-28 [CA 102: 9267z] and Neftekhimiya 24 (2), 246 [CA 101 : 40727c] and Neftekhimiya 27 (5), 703-9) [CA 108: 97496a].

Als Antioxidantien bezeichnet man Substanzen, welche - in geringen Mengen zugegeben - einen zeitweiligen Stillstand oder zumindest eine erhebliche Verzögerung der oxidativen Vorgänge bei dem zu schützenden Produkt bewirken.Antioxidants are substances that - added in small amounts - cause a temporary standstill or at least a considerable delay in the oxidative processes in the product to be protected.

Die bisher aus der Literatur bekannten 2,6-Di-tert.-Butyl­phenyl-Derivate eignen sich als Stabilisator gegen thermo­oxidativen oder lichtinduzierten Abbau für Polyolefin-­Copolymere, Polystyrol, Acryl-Butadien-Styrol, Polyvinyl­chlorid, Polyester, Cellulose-Derivate, Elastomere, Kleb­stoffe, techn. Fette, Mineralöle, Lacke und Farben. Einige Verbindungen wie z.B. Irganox 1076 [3-(3.5-Di-­tert.-butyl-4-hydroxyphenyl)-propionsäureoctadecylester] erhielten die FDA-Zulassung für Lebensmittelverpackungen.The 2,6-di-tert-butylphenyl derivatives known to date from the literature are suitable as stabilizers against thermooxidative or light-induced degradation for polyolefin copolymers, polystyrene, acrylic butadiene styrene, polyvinyl chloride, polyester, cellulose derivatives, elastomers, Adhesives, technical Greases, mineral oils, paints and paints. Some connections such as Irganox 1076 [octadecyl 3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionate] received FDA approval for food packaging.

Als Pharmakon findet bereits eine Substanz mit einem sterisch gehinderten Alkylphenol Anwendung. Probucol (Lurcelle®),

Figure imgb0005
ursprünglich in der Kunststoff- und Kautschuk- Industrie als Weichmacher bzw. Antioxidans verwendet, zeigt eine hypocholesterinämische Wirkung bei Mäusen, Ratten, Hunden, Affen und am Menschen.A substance with a sterically hindered alkylphenol is already used as a pharmaceutical. Probucol (Lurcelle®),
Figure imgb0005
 originally used in the plastics and rubber industry as a plasticizer or antioxidant, shows a hypocholesterolemic effect in mice, rats, dogs, monkeys and in humans.

Mit der Reduktion des Serumcholesterins ist eine vermin­derte Ausscheidung neutraler Sterole, Totalsterole und Gallensäuren in die Faeces verbunden, wobei gleichzeitig die Cholesterin-7-alpha-hydroxylaseaktivität vermindert ist.The reduction in serum cholesterol is associated with a reduced excretion of neutral sterols, total sterols and bile acids in the faeces, while cholesterol-7-alpha-hydroxylase activity is reduced at the same time.

Der genaue Wirkmechanismus ist nicht bekannt.The exact mechanism of action is not known.

Die im Tierversuch nachweisbare antiatherosklerotische Wirkung von Probucol beruht auf seiner Eigenschaft als Antioxidans: D. Steinberg et al. konnten in in vivo-­Experimenten an WHHL-Kaninchen zeigen, daß Probucol die oxidative Modifizierung der LDL-Partikel und die Bildung von cholesterinesterreichen makrophagozytären Schaumzellen in Frühläsionen der Arterienwand verhindert. (D. Steinberg et al., N Engl J Med 320, 915 - 924 (1989))The antiatherosclerotic effect of Probucol, which can be demonstrated in animal experiments, is based on its property as an antioxidant: D. Steinberg et al. were able to show in in vivo experiments on WHHL rabbits that probucol prevents the oxidative modification of the LDL particles and the formation of macrophagocytic foam cells rich in cholesterol esters in early lesions of the artery wall. (D. Steinberg et al., N Engl J Med 320, 915-924 (1989))

Die Resorption der stark lipophilen Verbindung ist gering; die Eliminierung aus den Geweben ist äußert langsam, die Ausscheidung erfolgt hauptsächlich über die Faeces [M.N.Cayen Pharmacol. Ther. 29, 157 (1985)].The absorption of the strongly lipophilic compound is low; the elimination from the tissues is extremely slow, the elimination takes place mainly via the faeces [MNCayen Pharmacol. Ther. 29 , 157 (1985)].

Die erfindungsgemäßen Verbindungen sind Stabilisatoren von Lipoprotein-Partikeln und blockieren die Reacylierung von LDL-Cholesterin in Makrophagen. Sie eignen sich daher alleine oder in Kombination mit Antihyperlipidämika zur Prophylaxe und Therapie von Erkrankungen, die durch er­höhtes bzw. durch Oxidation verändertes Serumcholesterin verursacht werden, wie koronare Herzkrankheiten, Atheros­clerose, Hyperlipoproteinämie und ähnliche Erkrankungen.The compounds according to the invention are stabilizers of lipoprotein particles and block the reacylation of LDL cholesterol in macrophages. They are therefore suitable on their own or in combination with antihyperlipidemics for the prophylaxis and therapy of diseases which are caused by increased or changed serum cholesterol, such as coronary heart diseases, atherosclerosis, hyperlipoproteinemia and similar diseases.

Zur Herstellung von Arzneimitteln werden die Verbindungen der allgemeinen Formel I in an sich bekannter Weise mit geeigneten pharmazeutischen Trägersubstanzen, Aroma-, Geschmacks- und Farbstoffen gemischt und beispielsweise als Tabletten oder Dragees ausgeformt oder unter Zugabe entsprechender Hilfsstoffe in Wasser oder Öl, wie z.B. Olivenöl, suspendiert oder gelöst.For the preparation of medicaments, the compounds of the general formula I are mixed in a manner known per se with suitable pharmaceutical carriers, flavorings, flavors and colors and shaped, for example, as tablets or dragées or with the addition of appropriate auxiliaries in water or oil, such as olive oil, for example. suspended or dissolved.

Die Substanzen der allgemeinen Formel I können in flüssiger oder fester Form oral und parenteral appliziert werden. Als Injektionsmedium kommt vorzugsweise Wasser zur Anwendung, welches die bei Injektionslösungen üblichen Stabilisierungsmittel, Lösungsvermittler und/oder Puffer enthält. Derartige Zusätze sind z.B. Tartrat- oder Borat-­Puffer, Ethanol, Dimethylsulfoxid, Komplexbildner (wie Ethylendiamintetraessigsäure), hochmolekulare Polymere (wie flüssiges Polyethylenoxid) zur Viskositätsregulierung oder Polyethylen-Derivate von Sorbitanhydriden.The substances of the general formula I can be administered orally and parenterally in liquid or solid form. Water is preferably used as the injection medium, which contains the stabilizers, solubilizers and / or buffers customary for injection solutions. Such additives are e.g. Tartrate or borate buffers, ethanol, dimethyl sulfoxide, complexing agents (such as ethylenediaminetetraacetic acid), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity regulation or polyethylene derivatives of sorbitan hydrides.

Feste Trägerstoffe sind z.B. Stärke, Lactose, Mannit, Methylcellulose, Talkum, hochdisperse Kieselsäure, höher­molekulare Fettsäuren (wie Stearinsäure), Gelatine, Agar-­Agar, Calciumphosphat, Magnesiumstearat, tierische und pflanzliche Fette oder feste hochmolekulare Polymere (wie Polyethylenglykole). Für die orale Applikation geeignete Zubereitungen können gewünschtenfalls Geschmacks- und Süßstoffe enthalten.Solid carriers are e.g. Starch, lactose, mannitol, methyl cellulose, talc, highly disperse silica, higher molecular fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats or solid high molecular weight polymers (such as polyethylene glycols). Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.

Die verabreichte Dosierung hängt vom Alter, der Gesundheit und dem Gewicht des Empfängers, dem Ausmaß der Krankheit, der Art gleichzeitiger gegebenenfalls durchgeführter weiterer Behandlungen, der Häufigkeit der Behandlungen und der Art der gewünschten Wirkung ab. Üblicherweise beträgt die tägliche Dosis der aktiven Verbindung 0.1 bis 10 mg/kg Körpergewicht.The dosage administered depends on the age, health and weight of the recipient, the extent of the disease, the type of further treatments which may be carried out at the same time, the frequency of the treatments and the type of effect desired. The daily dose of the active compound is usually 0.1 to 10 mg / kg body weight.

Di-butylierte Hydroxyphenyl-Derivate der Formel I mit mindestens einer Carbonyl-Gruppe als Amid- oder Harnstoff und deren Derivate können nach bekannten Syntheseverfahren erhalten werden, beispielsweise durch die Umsetzung einer Carbonsäure oder eines Derivats (Formel II) mit einem Amin der allgemeinen Formel III

Figure imgb0006
in denen
A und C sowie der Substituent R die in Formel I ange­gebene Bedeutung haben.Di-butylated hydroxyphenyl derivatives of the formula I with at least one carbonyl group as amide or urea and their derivatives can be obtained by known synthetic processes, for example by reacting a carboxylic acid or a derivative (formula II) with an amine of the general formula III
Figure imgb0006
 in which
A and C and the substituent R have the meaning given in formula I.

Die Umsetzung erfolgt in der Regel in einem inerten Lösungsmittel wie einem Kohlenwasserstoff, Dimethylform­amid oder in Ether.The reaction is usually carried out in an inert solvent such as a hydrocarbon, dimethylformamide or in ether.

Vorzugsweise verwendet man äquimolare Mengen an Amin und Carbonsäure in Gegenwart äquimolarer Mengen einer Base wie einem tert. organ. Amin bevorzugt Triethylamin, Alkali­bicarbonat-, Hydroxyd oder - Carbonat.Equimolar amounts of amine and carboxylic acid are preferably used in the presence of equimolar amounts of a base such as a tert. organ. Amine prefers triethylamine, alkali bicarbonate, hydroxide or carbonate.

Als Derivate der Carbonsäure (Formel II) können das Säure­chlorid oder ein Ester dienen.The acid chloride or an ester can serve as derivatives of the carboxylic acid (formula II).

Für die Umsetzung der freien Carbonsäure ist in der Regel die Anwesenheit von POCl₃, SOCl₂ oder PCl₃ erforderlich für die Umsetzung eines Carbonsäure-Esters mit dem Amin ein basischer Katalysator, bevorzugt ein Alkalialkoholat. In vielen Fällen gelingt auch die Reaktion der Carbonsäure mit einem Amin in einem Lösungsmittel wie z.B. Xylol durch Erwärmen unter Rückfluß am Wasserabscheider.For the reaction of the free carboxylic acid, the presence of POCl₃, SOCl₂ or PCl₃ is usually necessary for the reaction of a carboxylic acid ester with the amine, a basic catalyst, preferably an alkali alcoholate. In many cases, the reaction of the carboxylic acid with an amine in a solvent such as xylene is also possible by heating under reflux on a water separator.

Bei der Darstellung der Diamide werden zwei Äquivalente Carbonsäure (Formel II) pro Di-Amin-Komponente (IV) beziehungsweise zwei Äquivalente Amin (III) pro Di-­Carbonsäure-Komponente (V) eingesetzt, je nachdem, ob es sich um die Strukturen e) oder f) handelt.In the preparation of the diamides, two equivalents of carboxylic acid (formula II) per di-amine component (IV) or two equivalents of amine (III) per di-carboxylic acid component (V) are used, depending on whether the structures e ) or f).

Die Versuchsbedingungen bleiben identisch wie bei den oben beschriebenen Monoamiden.

Figure imgb0007
HO₂C------D-----CO₂H
R, R′ entsprechen der in Formel I angegebenen Bedeutung.The test conditions remain the same as for the monoamides described above.
Figure imgb0007
 HO₂C ------ D ----- CO₂H
R, R 'correspond to the meaning given in formula I.

Das Teilstück Ⓓ entspricht der in Formel I angegebenen Bedeutung.The section Ⓓ corresponds to the meaning given in formula I.

Die Harnstoff-Derivate können durch Umsetzung des Amins der allgemeinen Formel III

Figure imgb0008
mit Phosgen dargestellt werden. Dabei wird in einem Überschuß an Amin gearbeitet.The urea derivatives can by reacting the amine of the general formula III
Figure imgb0008
 can be represented with phosgene. An excess of amine is used.

Die entsprechende Umsetzung mit Thiocarbonylchlorid (Thio­phosgen) und 4 Äquivalenten des Amins der allgmeinen Formel III führt zum Thioharnstoff. Die Thiocarbamidsäure­chloride werden als Zwischenstufe nicht isoliert (vgl. T. J. Pullukat et al., Tetrahedron Lett. 1967, 1953).The corresponding reaction with thiocarbonyl chloride (thiophosgene) and 4 equivalents of the amine of the general formula III leads to the thiourea. The thiocarbamic acid chlorides are not isolated as an intermediate (cf. TJ Pullukat et al., Tetrahedron Lett. 1967 , 1953).

Symmetrische Harnstoff-Derivate lassen sich auch durch Carbonilierung von primären Aminen (Aryl- u. Alkylamine) mit Kohlenmonoxid in Gegenwart eines Katalysators wie Selen oder Schwefel darstellen (vgl. Sonoda et al., J.Am. Chem.Soc., 93, 6344 (1971) und Franz et al. J.Org.Chem. 26, 3309 (1961).Symmetrical urea derivatives can also be prepared by carbonylation of primary amines (arylamines and alkylamines) with carbon monoxide in the presence of a catalyst such as selenium or sulfur (cf. Sonoda et al., J.Am. Chem. Soc., 93 , 6344 (1971) and Franz et al. J. Org. Chem. 26 , 3309 (1961).

Symmetrische Thioharnstoffe entstehen ebenfalls durch Ein­wirkung von Schwefelkohlenstoff auf Amine, bevorzugt auf aromatische Amine unter Abspaltung von Schwefelwasser­stoff. Als Lösungsmittel bewähren sich Alkohol und Aceton (vgl. Houben-Weyl IX, 885 sowie Deposited. Doc., Viniti 6343-82, 93-8, C.A. 100 (19): 156 325 d).Symmetrical thioureas are also formed by the action of carbon disulphide on amines, preferably aromatic amines, with elimination of hydrogen sulfide. Alcohol and acetone have proven to be suitable solvents (cf. Houben-Weyl IX, 885 and Deposited. Doc., Viniti 6343-82, 93-8, CA 100 (19): 156 325 d).

Die für die nachstehenden Beispiele am häufigsten an­gewandte Methode zur Darstellung von symmetrisch wie auch unsysmmetrisch substituierten Harnstoffen stellt die Addition eines Amins (III) an ein Isocyanat (VI) dar (X = O).

Figure imgb0009
The most frequently used method for the preparation of symmetrically as well as unsymmetrically substituted ureas for the examples below is the addition of an amine (III) to an isocyanate (VI) (X = O).
Figure imgb0009

Die Umsetzungen von Isothiocyanaten (X = S) mit einem primären Amin ergibt das Thioharnstoff-Derivat (analog Satchell et al., Chem. Soc. Rev. 4, 231-50 (1975)).The reactions of isothiocyanates (X = S) with a primary amine gives the thiourea derivative (analog Satchell et al., Chem. Soc. Rev. 4 , 231-50 (1975)).

Diese Methode liefert hervorrangende Ausbeuten, wenn in aprotischen Lösungsmitteln, bevorzugt in Kohlenwasser­stoffen oder auch in Ether gearbeitet wird. (Houben-Weyl VIII, 157).This method provides excellent yields when working in aprotic solvents, preferably in hydrocarbons or in ether. (Houben-Weyl VIII, 157).

Die in der vorliegenden Erfindung beschriebenen Thioamid- und Thioharnstoffderivate können ebenso aus den Carbonyl­verbindungen mit Phosphorpentasulfid dargestellt werden.The thioamide and thiourea derivatives described in the present invention can also be prepared from the carbonyl compounds with phosphorus pentasulfide.

Man verwendet pro Carbonylfunktion etwa 2 Äquivalente Pentasulfid in wasserfreien aprotischen Lösungsmitteln, bevorzugt Kohlenwasserstoffen wie Xylol.About 2 equivalents of pentasulfide in anhydrous aprotic solvents, preferably hydrocarbons such as xylene, are used per carbonyl function.

Als geeigneter erwies sich die Umsetzung mit Lawesson's Reagenz (2,4-Bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphos­phetan-2,4-disulfid) in geringem Überschuß (1.1 bis zu 2.0 Äquivalente) in aprotischen Lösungsmitteln, bevorzugt in Toluol oder Xylol bei erhöhten Temperaturen.The reaction with Lawesson's reagent (2,4-bis- (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide) in a slight excess (1.1 to 2.0 equivalents) proved to be more suitable. in aprotic solvents, preferably in toluene or xylene at elevated temperatures.

Gegenstand der Erfindung sind auch neue Verbindungen der Formel I, insbesondere die folgenden Verbindungen:
Bevorzugte Verbindungen der allgemeinen Formel I:
N-[2-[3,5-Di-tert.-butyl-4-hydroxyphenyl]ethyl]-3,5-di-­tert.-butyl-4-hydroxybenzamid
3,5-Di-tert.-butyl-4-Hydroxyphenylessigsäure-(3,5-di-­tert.-butyl-4-hydroxyphenyl)methyl-amid
3,3′-Thiobis-[N-[[3,5-di-tert.-butyl-4-hydroxyphenyl]­ethyl]propionsäureamid
3-(3,5-Di-tert.-butyl-4-hydroxyphenyl)propionsäure-[2-­(3,5-di-tert.-butyl-4-hydroxyphenyl)ethyl-amid
3-(3,5-Di-tert.-butyl-4-hydroxyphenyl)zimtsäure-[2-(3,5-­di-tert.-butyl)-4-hydroxyphenyl)ethyl]amid
N,N′-Bis-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)ethyl]­harnstoff
N,N′-Bis-[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)ethyl]­thioharnstoff
N,N′-Diethyl-N,N′-bis-(3,5-di-tert.-butyl-4-hydroxy­phenethyl)hexansäureamid
3,3-Thiobis-[N-[[3,5-di-tert.-butyl-4-hydroxyphenyl]­ethyl]propionsäureamidThe invention also relates to new compounds of the formula I, in particular the following compounds:
Preferred compounds of the general formula I:
N- [2- [3,5-di-tert-butyl-4-hydroxyphenyl] ethyl] -3,5-di-tert-butyl-4-hydroxybenzamide
3,5-di-tert-butyl-4-hydroxyphenylacetic acid- (3,5-di-tert-butyl-4-hydroxyphenyl) methyl amide
3,3'-Thiobis [N - [[3,5-di-tert-butyl-4-hydroxyphenyl] ethyl] propionic acid amide
3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionic acid- [2- (3,5-di-tert-butyl-4-hydroxyphenyl) ethyl amide
3- (3,5-di-tert-butyl-4-hydroxyphenyl) cinnamic acid- [2- (3,5-di-tert-butyl) -4-hydroxyphenyl) ethyl] amide
N, N'-bis- [2- (3,5-di-tert-butyl-4-hydroxyphenyl) ethyl] urea
N, N'-bis- [2- (3,5-di-tert-butyl-4-hydroxyphenyl) ethyl] thiourea
N, N'-diethyl-N, N'-bis- (3,5-di-tert-butyl-4-hydroxyphenethyl) hexanoic acid amide
3,3-thiobis [N - [[3,5-di-tert-butyl-4-hydroxyphenyl] ethyl] propionic acid amide

Die folgenden Beispiele erläutern die Erfindung.The following examples illustrate the invention.

Die Ausgangsstoffe sind bekannt oder können, sofern sie neu sind, in Analogie zu den bekannten Verbindungen in an sich bekannter Weise hergestellt werden.The starting materials are known or, if they are new, can be prepared in a manner known per se in analogy to the known compounds.

Beispiel 1example 1 3-(3,5-Di-tert.butyl-4-hydroxyphenyl)-propionitril3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionitrile

Ein Gemisch aus 206.3 g (1 mol) 2,6-Di-tert.-butylphenol, 4.8 g pulv. Natriumborhydrid und 262 ml (4 mol) Acryl­nitril wird 16 h im Ölbad auf 90°C erwärmt (leichter Rück­fluß). Man kühlt ab, rührt in 1 l Wasser ein, säuert an und gibt 900 ml Methylenchlorid zu. Danach saugt man das gebildete Produkt ab, trennt, wäscht die Wasserphase zweimal mit wenig Methylenchlorid, vereint die Methylen­chloridphasen, trocknet sie und engt ein. Das Rohprodukt wird auf der Nutsche zweimal mit je 250 ml Ligroin gewaschen.
Ausbeute: 203.6 g (78 % d. Theorie)
Schmp. 110-113°C
Lit.: Sumitomo, Jap. Kokai 75, 71 638A mixture of 206.3 g (1 mol) of 2,6-di-tert-butylphenol, 4.8 g of powdered sodium borohydride and 262 ml (4 mol) of acrylonitrile is heated in an oil bath at 90 ° C. for 16 h (gentle reflux). It is cooled, stirred in 1 l of water, acidified and 900 ml of methylene chloride are added. The product formed is then filtered off with suction, separated, the water phase is washed twice with a little methylene chloride, the methylene chloride phases are combined, dried and concentrated. The crude product is washed twice on the suction filter with 250 ml of ligroin.
Yield: 203.6 g (78% of theory)
Mp 110-113 ° C
Lit .: Sumitomo, Jap. Kokai 75 , 71 638

Beispiel 2Example 2 3-(4-Hydroxy-3,5-di-tert.-butyl-phenyl)propionsäure3- (4-hydroxy-3,5-di-tert-butyl-phenyl) propionic acid

Ein Gemisch aus 190 ml Wasser, 148.0 g (3.7 mol) NaOH, 800 ml Ethanol und 95.6 g (0.37 mol) des Propionitrils (s.o.) wird unter Stickstoff 18 h auf Rückflußtemperatur erhitzt. Dann kühlt man ab, säuert mit 6 N Salzsäure auf pH 2 an, saugt ab und wäscht den Filterkuchen mit Wasser. Nach Umkristallisation aus 66proz. Alkohol erhält man 95.0 g (92 % d. Theorie) Carbonsäure.
Schmp.: 169.5-170°CA mixture of 190 ml of water, 148.0 g (3.7 mol) of NaOH, 800 ml of ethanol and 95.6 g (0.37 mol) of the propionitrile (see above) is heated to the reflux temperature under nitrogen for 18 h. Then it is cooled, acidified to pH 2 with 6 N hydrochloric acid, suction filtered and the filter cake is washed with water. After recrystallization from 66 percent. Alcohol gives 95.0 g (92% of theory) of carboxylic acid.
Mp: 169.5-170 ° C

Beispiel 3Example 3 4-Hydroxy-3,5-di-tert.butyl-benzylchlorid4-hydroxy-3,5-di-tert-butyl-benzyl chloride

Man löst 52.8 g (0.256 mol) 2,6-Di-tert.-butylphenol in 200 ml n-Heptan, gibt 250 ml 37proz. Formalinlösung und 500 ml konz. Salzsäure zu, spült mit Stickstoff und rührt 18 h bei Rückflußtemperatur. Nach dem Abkühlen trennt man die org. Phase ab, extrahiert die wässrige Phase mit n-­Heptan und wäscht die vereinten Heptanphasen mit Wasser. Nach Trocknen mittels Na₂SO₄ wird i. Vak. eingedampft und der Rückstand i. Vak. destilliert.
Sdp.: 132-134°C/0.01 Torr
Ausbeute: 46.2 g (71 % d. Theorie)
Lit.: Neureither, J.Org.Chem. 28, 3486 (1963)52.8 g (0.256 mol) of 2,6-di-tert-butylphenol are dissolved in 200 ml of n-heptane, 250 ml of 37 percent are added. Formalin solution and 500 ml conc. Hydrochloric acid, flushed with nitrogen and stirred at reflux temperature for 18 h. After cooling, the org. Phase, the aqueous phase is extracted with n-heptane and the combined heptane phases are washed with water. After drying using Na₂SO₄ i. Vac. evaporated and the residue i. Vac. distilled.
Bp .: 132-134 ° C / 0.01 Torr
Yield: 46.2 g (71% of theory)
Lit .: Neureither, J.Org.Chem. 28 , 3486 (1963)

Beispiel 4Example 4 4-Hydroxy-3,5-di-tert.-butylbenzylcyanid4-hydroxy-3,5-di-tert-butylbenzyl cyanide

Zu einer 80-85°C heißen Mischung aus 38.4 g (0.71 mol) Natriumcyanid, 50 ml Wasser und 72 ml Ethanol tropft man innerhalb 1 h eine Lösung aus 104.5 g (0.41 mol) 4-Hydroxy-3,5-di-tert.-butylbenzylchlorid und 155 ml Ethanol. Anschließend hält man weitere 3 h auf Rückfluß­temperatur, kühlt ab und saugt anorgan. Material ab. Die flüssige Phase wird eingedampft, der Eindampfrückstand mit Wasser versetzt und mit Ether extrahiert. Man trocknet die Etherphase (Na₂SO₄), dampft ein und bringt durch Ligroin-­Zugabe zur Kristallisation.
Ausbeute: 61.1 g (61 % d. Theorie)
Schmp.: 109-110°C
analog Fuson und Rabjohn, Org. Synth. Vol. 25, 66.A solution of 104.5 g (0.41 mol) of 4-hydroxy-3,5-di-tert is added dropwise to an 80-85 ° C. mixture of 38.4 g (0.71 mol) of sodium cyanide, 50 ml of water and 72 ml of ethanol .-butylbenzyl chloride and 155 ml of ethanol. The mixture is then kept at the reflux temperature for a further 3 hours, cooled and suctioned off inorganically. Material. The liquid phase is evaporated, the evaporation residue is mixed with water and extracted with ether. The ether phase (Na₂SO₄) is dried, evaporated and brought to crystallization by adding ligroin.
Yield: 61.1 g (61% of theory)
Mp: 109-110 ° C
analogous to Fuson and Rabjohn, Org. Synth. Vol. 25 , 66.

Beispiel 5Example 5 4-Hydroxy-3,5-dit-tert.-butylphenethylamin4-hydroxy-3,5-dit-tert-butylphenethylamine

Zu einer Suspension aus 19.0 g (0.5 mol) LiAlH₄ und 600 ml absol. Ether tropft man unter Stickstoff eine Lösung aus 60.0 g (0.245 mol) 4-Hydroxy-3,5-di-tert.-butylbenzyl­cyanid und 400 ml absol. Ether. Man rührt weitere 4 h bei Rückflußtemperatur, zersetzt dann mit Natronlauge und Wasser und saugt ab. Die Etherphase wird getrocknet mit Natriumsulfat und eingedampft.
Ausbeute: 59 g (97 % d. Theorie)
Schmp.: 106-108°C (Umkrist. aus Ligroin).To a suspension of 19.0 g (0.5 mol) LiAlH₄ and 600 ml absolute. A solution of 60.0 g (0.245 mol) of 4-hydroxy-3,5-di-tert-butylbenzyl cyanide and 400 ml of absolute is added dropwise under nitrogen. Ether. The mixture is stirred for a further 4 h at the reflux temperature, then decomposed with sodium hydroxide solution and water and filtered off with suction. The ether phase is dried with sodium sulfate and evaporated.
Yield: 59 g (97% of theory)
Mp: 106-108 ° C (recrystallized from ligroin).

Beispiel 6Example 6 3-(3,5-Di-tert.-butyl-4-hydroxyphenyl)-propionsäure-[2-­(3,5-di-tert.-butyl-4-hydroxyphenyl)ethyl]amid3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionic acid- [2- (3,5-di-tert-butyl-4-hydroxyphenyl) ethyl] amide

Eine Lösung von 7.48 g (0.03 mol) 3-(4-Hydroxy-3,5-di-­tert.-butylphenyl)propionsäure und 8.35 g (0.03 mol) 4-Hydroxy-3,5-di-tert.-butylphenethylamin in 250 ml Xylol wird 56 h am Wasserabscheider unter Rückfluß erhitzt; weder Carbonsäure noch Amin sind nach dieser Zeit dünn­schichtchromatographisch nachweisbar.
Der Ansatz wird eingeengt, der Rückstand kristallisiert durch Verreiben mit Ligroin.
Ausbeute: 10.9 g (71 % d. Theorie)
Schmp.: 172°CA solution of 7.48 g (0.03 mol) of 3- (4-hydroxy-3,5-di-tert-butylphenyl) propionic acid and 8.35 g (0.03 mol) of 4-hydroxy-3,5-di-tert-butylphenethylamine in 250 ml of xylene is refluxed for 56 h on a water separator; neither carboxylic acid nor amine can be detected by thin layer chromatography after this time.
The mixture is concentrated, the residue crystallizes by trituration with ligroin.
Yield: 10.9 g (71% of theory)
Mp: 172 ° C

Beispiel 7Example 7 3,5-Di-tert.-butyl-4-hydroxy-zimtsäure3,5-di-tert-butyl-4-hydroxy-cinnamic acid

Eine Lösung von 75.5 g (0.3 mol) 3,5-Di-tert.-butyl-4-­hydroxybenzaldehyd, 270 ml Pyridin, 10 ml Piperidin und 100 g (0.95 mol) Malonsäure wird 2 h auf 85°C unter Stick­stoff unter Rühren erwärmt; anschließend rührt man schnell in 750 g Eis und 150 ml konz. Salzsäure ein. Das entstehende Öl nimmt man in Methylenchlorid auf, extra­hiert viermal mit 2 N Salzsäure, wäscht neutral, trocknet über Natriumsulfat und dampft i. Vak. ein. Nach Umkristal­lisation erhält man das Zimtsäurederivat als Kristallisat mit einem Schmelzpunkt von 198-201°C
Ausbeute: 59 %.A solution of 75.5 g (0.3 mol) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde, 270 ml of pyridine, 10 ml of piperidine and 100 g (0.95 mol) of malonic acid is stirred at 85 ° C. for 2 hours under nitrogen warmed; then quickly stirred in 750 g of ice and 150 ml of conc. Hydrochloric acid. The resulting oil is taken up in methylene chloride, extracted four times with 2 N hydrochloric acid, washed neutral, dried over sodium sulfate and evaporated i. Vac. a. After recrystallization, the cinnamic acid derivative is obtained as crystals with a melting point of 198-201 ° C.
Yield: 59%.

Beispiel 8Example 8 3-(3,5-Di-tert.-butyl-4-hydroxyphenyl)zimtsäure-[2-(3,5-­di-tert.-butyl-4-hydroxyphenyl)ethyl]amid3- (3,5-di-tert-butyl-4-hydroxyphenyl) cinnamic acid- [2- (3,5-di-tert-butyl-4-hydroxyphenyl) ethyl] amide

Zu einer Lösung aus 4.44 g (0.016 mol) 3,5-Di-tert.-butyl-­4-hydroxyzimtsäure und 4.0 g (0.016 mol) 4-Hydroxy-3,5-di-­tert.-butylphenethylamin in 100 ml Pyridin gibt man 1.1 g (0.008 mol) Phosphortrichlorid und erwärmt 10 h auf 90°C.To a solution of 4.44 g (0.016 mol) of 3,5-di-tert-butyl-4-hydroxycinnamic acid and 4.0 g (0.016 mol) of 4-hydroxy-3,5-di-tert-butylphenethylamine in 100 ml of pyridine 1.1 g (0.008 mol) of phosphorus trichloride and heated at 90 ° C. for 10 h.

Nach dem Einengen wird der Rückstand in Ether aufgenommen, mehrmals mit 0.5 N Natronlauge, anschließend mit 0.5 N Salzsäure und Wasser gewaschen und eingeengt.
Ausbeute: 71 %
Schmp.: 245°CAfter concentration, the residue is taken up in ether, washed several times with 0.5 N sodium hydroxide solution, then with 0.5 N hydrochloric acid and water and concentrated.
Yield: 71%
Mp: 245 ° C

Beispiel 9Example 9 3,5-Di-tert.-butyl-4-hydroxy-phenethyl-isocyanat3,5-di-tert-butyl-4-hydroxyphenethyl isocyanate

Eine Lösung aus 24.94 g (0.1 mol) 3,5-Di-tert.-butyl-4-­hydroxy-phenethylamin und 100 ml absol. Toluol wird zunächst bis zur sauren Reaktion mit Chlorwasserstoff begast. Dann erhitzt man auf 100°C und leitet langsam 49.4 g (0.5 mol) Phosgen ein. Anschließend hält man 45 min auf Rückflußtemperatur. Nach Stehen über Nacht wird i. Vak. das Toluol abdestilliert, wobei man das Isocyanat als schwarzes Öl erhält, das ohne weitere Aufreinigung für die Harnstoff-Synthese verwendet werden kann.A solution of 24.94 g (0.1 mol) of 3,5-di-tert-butyl-4-hydroxy-phenethylamine and 100 ml of absolute. Toluene is first gassed with hydrogen chloride until an acidic reaction occurs. The mixture is then heated to 100 ° C. and 49.4 g (0.5 mol) of phosgene are slowly introduced. The mixture is then held at the reflux temperature for 45 minutes. After standing overnight i. Vac. the toluene is distilled off, the isocyanate being obtained as a black oil which can be used for the urea synthesis without further purification.

Beispiel 10Example 10 N,N′-Bis-(3,5-di-tert.-butyl-4-hydroxy-phenylethyl)-­harnstoffN, N'-bis (3,5-di-tert-butyl-4-hydroxy-phenylethyl) urea

Zu einer Lösung aus 19.9 g (80 mmol) 3,5-Di-tert.-butyl-4-­hydroxyphenethylamin in 100 ml absol. Ether tropft man unter Stickstoff eine Lösung aus 22 g (80 mmol) des rohen Isocyanats und 40 ml absol. Ether. Nachdem die schwach exotherme Reaktion abgeklungen ist, fällt ein kristalliner Niederschlag aus, der abgesaugt, getrocknet und zweimal aus Ethanol umkristallisiert wird.
Ausbeute: 27.8 g, (66 % d. Theorie)
Schmp.: 191-192°CTo a solution of 19.9 g (80 mmol) of 3,5-di-tert-butyl-4-hydroxyphenethylamine in 100 ml of absolute. A solution of 22 g (80 mmol) of the crude isocyanate and 40 ml of absolute is added dropwise under nitrogen. Ether. After the weakly exothermic reaction has subsided, a crystalline precipitate precipitates, which is filtered off with suction, dried and recrystallized twice from ethanol.
Yield: 27.8 g, (66% of theory)
Mp: 191-192 ° C

Beispiel 11Example 11 2-(3,5-Di-tert.-butyl-4-hydroxy-phenoxy)-2-methyl-propion­säure2- (3,5-di-tert-butyl-4-hydroxy-phenoxy) -2-methyl-propionic acid

Unter Stickstoff mischt man 50.0 g (225 mmol) 2,6-Di-­tert.-butyl-hydrochinon mit 500 ml Butanon-2 und 48.4 g (350 mmol) Kaliumcarbonat, rührt 2 h bei 80°C, gibt eine Spatelspitze Kaliumjodid sowie 68.2 g (350 mmol) 2-Brom-2-­methylpropionsäureethylester zu und hält 4 h auf Rückfluß­temperatur. Man saugt ab, dampft i. Vak. ein und destil­liert den Rückstand im Hochvakuum. Zwischen 143°C und 144°C/0.005 Torr erhält man 50.0 g (66 % d. Theorie) farbloses, langsam erstarrendes Produkt, das im Kältebad aus Ligroin umkristallisiert wird.
Schmp.: 50-51°C50.0 g (225 mmol) of 2,6-di-tert-butyl-hydroquinone are mixed with nitrogen with 500 ml of 2-butanone and 48.4 g (350 mmol) of potassium carbonate, the mixture is stirred at 80 ° C. for 2 h, a spatula tip of potassium iodide and 68.2 g (350 mmol) of 2-bromo-2-methylpropionic acid ethyl ester and holds at reflux temperature for 4 h. You suck off, steam i. Vac. and distilled the residue under high vacuum. Between 143 ° C and 144 ° C / 0.005 Torr, 50.0 g (66% of theory) of colorless, slowly solidifying product is obtained, which is recrystallized from ligroin in a cold bath.
Mp: 50-51 ° C

17.0 g (50 mmol) des Ethylesters werden in 125 ml Ethanol und 125 ml 2 N Natronlauge (0.25 mol) 30 min auf Siedetem­peratur erwärmt, nach dem Abkühlen mit 125 ml 2 N Salz­säure (0.25 mol) versetzt. Der ausgefallene Niederschlag ergibt 10.7 g (69 % d. Theorie) Säure mit dem Schmp. 122-­123°C.17.0 g (50 mmol) of the ethyl ester are in 125 ml of ethanol and 125 ml of 2 N sodium hydroxide solution (0:25 mol) of 30 min to boiling temperature, mixed after cooling with 125 ml of 2 N hydrochloric acid (12:25 mol). The precipitate formed gives 10.7 g (69% of theory) of acid with a melting point of 122-123 ° C.

Beispiel 12Example 12 N,N′-Bis-(3,5-di-tert.-butyl-4-hydroxyphenethyl)-thioharn­stoffN, N'-bis (3,5-di-tert-butyl-4-hydroxyphenethyl) thiourea

Zu einer Lösung von 2.62 g (5 mmol) N,N′-Bis-(3,5-di-­tert.-butyl-4-hydroxyphenethyl)-harnstoff in 20 ml absol. Toluol gibt man unter Stickstoff 1.2 g (3 mmol) Lawesson's Reagenz (2,4-Bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphos­phetan-2,4-disulfid).To a solution of 2.62 g (5 mmol) of N, N'-bis (3,5-di-tert-butyl-4-hydroxyphenethyl) urea in 20 ml of absolute. Toluene is added under nitrogen 1.2 g (3 mmol) Lawesson's reagent (2,4-bis- (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide).

Danach erwärmt man auf 100°C und läßt 1.5 h bei dieser Temperatur rühren. Nach dem Abkühlen wird die Lösung ein­geengt und der Rückstand mehrmals aus Ether/Isohexan um­kristallisiert.
Ausbeute: 63 %
Schmp.: 135-136°CThen heated to 100 ° C and allowed to stir for 1.5 h at this temperature. After cooling, the solution is concentrated and the residue is recrystallized several times from ether / isohexane.
Yield: 63%
Mp: 135-136 ° C

Beispiel 13Example 13

In analoger Weise wie in den Beispielen 6, 8, 10 bzw. 12 beschrieben erhält man:

Figure imgb0010
Figure imgb0011
Figure imgb0012
Figure imgb0013
Figure imgb0014
Figure imgb0015
 In an analogous manner to that described in Examples 6, 8, 10 and 12, the following is obtained:
Figure imgb0010
Figure imgb0011
Figure imgb0012
Figure imgb0013
Figure imgb0014
Figure imgb0015

Claims (4)

1. Arzneimittel, enthaltend eine Verbindung der allge­meinen Formel I
Figure imgb0016
 in der
A und C, die gleich oder verschieden sein können, eine Bindung oder eine gesättigte oder ungesättigte Kohlenwasserstoffkette mit 1-8 C-Atomen, die verzweigt oder unverzweigt sowie durch Heteroatome unterbrochen sein kann.
und B eine der folgenden Gruppen darstellt:
Figure imgb0017
 in denen
X Sauerstoff oder Schwefel,
R,R′, die gleich oder verschieden sein können,
Wasserstoff oder C₁-C₄ Alkyl, bedeuten,
und
D für eine ungesättigte oder gesättigte, verzweigte oder unverzweigte Kette mit ein bis 10 C-Atomen, die durch ein oder mehrere Heteroatome unterbrochen sein kann, steht, neben üblichen Träger- und Hilfs­stoffen.1. Medicament containing a compound of general formula I
Figure imgb0016
 in the
A and C, which can be the same or different, are a bond or a saturated or unsaturated hydrocarbon chain with 1-8 C atoms, which can be branched or unbranched and interrupted by heteroatoms.
and B represents one of the following groups:
Figure imgb0017
 in which
X oxygen or sulfur,
R, R ′, which can be the same or different,
Is hydrogen or C₁-C₄ alkyl,
and
D stands for an unsaturated or saturated, branched or unbranched chain with one to 10 carbon atoms, which can be interrupted by one or more heteroatoms, in addition to conventional carriers and auxiliaries. 2. Verwendung von Verbindungen gemäß Anspruch 1 als Antiarteriosklerotica.2. Use of compounds according to claim 1 as antiarteriosclerotics. 3. Verbindungen ausgewählt aus der Gruppe:
N-[2-[3,5-Di-tert.-butyl-4-hydroxyphenyl]ethyl]-3,5-­di-tert.-butyl-4-hydroxybenzamid
3,5-Di-tert.-butyl-4-Hydroxyphenylessigsäure-(3,5-di-­tert.-butyl-4-hydroxyphenyl)methyl-amid
3,3′-Thiobis-[N-[[3,5-di-tert.-butyl-4-­hydroxyphenyl]ethyl]propionsäureamid
3-(3,5-Di-tert.-butyl-4-hydroxyphenyl)propionsäure-­[2-(3,5-di-tert.-butyl-4-hydroxyphenyl)ethyl-amid
3-(3,5-Di-tert.-butyl-4-hydroxyphenyl)zimtsäure-[2-­(3,5-di-tert.-butyl)-4-hydroxyphenyl)ethyl]amid
N,N′-Bis-[2-(3,5-di-tert.-butyl-4-­hydroxyphenyl)ethyl]-harnstoff
N,N′-Bis-[2-(3,5-di-tert.-butyl-4-­hydroxyphenyl)ethyl]-thioharnstoff
N,N′-Diethyl-N,N′-bis-(3,5-di-tert.-butyl-4-hydroxy­phenethyl)hexansäureamid
3,3-Thiobis-[N-[[3,5-di-tert.-butyl-4-hydroxyphenyl]­ethyl]propionsäureamid3. Connections selected from the group:
N- [2- [3,5-di-tert-butyl-4-hydroxyphenyl] ethyl] -3,5-di-tert-butyl-4-hydroxybenzamide
3,5-di-tert-butyl-4-hydroxyphenylacetic acid- (3,5-di-tert-butyl-4-hydroxyphenyl) methyl amide
3,3'-Thiobis [N - [[3,5-di-tert-butyl-4-hydroxyphenyl] ethyl] propionic acid amide
3- (3,5-di-tert-butyl-4-hydroxyphenyl) propionic acid- [2- (3,5-di-tert-butyl-4-hydroxyphenyl) ethyl amide
3- (3,5-di-tert-butyl-4-hydroxyphenyl) cinnamic acid- [2- (3,5-di-tert-butyl) -4-hydroxyphenyl) ethyl] amide
N, N'-bis- [2- (3,5-di-tert-butyl-4-hydroxyphenyl) ethyl] urea
N, N'-bis- [2- (3,5-di-tert-butyl-4-hydroxyphenyl) ethyl] thiourea
N, N'-diethyl-N, N'-bis- (3,5-di-tert-butyl-4-hydroxyphenethyl) hexanoic acid amide
3,3-thiobis [N - [[3,5-di-tert-butyl-4-hydroxyphenyl] ethyl] propionic acid amide 4.Verfahren zur Herstellung von Arzneimitteln enthaltend Verbindungen der allgemeinen Formel I gemäß Anspruch 1, dadurch gekennzeichnet, daß man Verbindungen der Formel I mit üblichen pharmakologischen Träger- und/oder Hilfs­stoffen vermischt und zu Arzneimitteln verarbeitet.4. A process for the preparation of medicaments containing compounds of the general formula I according to claim 1, characterized in that compounds of the formula I are mixed with conventional pharmacological carriers and / or auxiliaries and processed into medicaments.
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DE59000750D1 (en) 1993-02-25
ATE84413T1 (en) 1993-01-15
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JPH0348648A (en) 1991-03-01
DE3920616A1 (en) 1991-01-03
GR3007513T3 (en) 1993-08-31

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